Paraneoplastic Syndromes in Patients with Keratinocyte Skin Cancer

Simple Summary The aim of the present review is to compile and evaluate the literature data on paraneoplastic syndromes (PNS) associated with keratinocyte skin cancer (KSC). Forty relevant entries were assembled, reporting a total of 41 PNS cases associated with a KSC (34 male). No review paper compiling this topic was found. Six distinct PNS entities were identified, and malignancy associated hypercalcemia (MAH; 78%), anemia (10%) and Bazex syndrome (5%) were the most frequently reported among them. 85% of the PNS were reported in association with SCC, 10% with BCC, and the rest with adnexal tumors. The median age of the patients at the time of PNS diagnosis was 58 years (range: five–83 years). KSC predisposing conditions, as scars (22%) or hidradenitis suppurativa (20%), were reported in >70% of the PNS cases. In conclusion, PNS are rarely reported in association with KSC, possibly reflecting a limited capacity of KSC to provoke overt PNS. Abstract A variety of well-characterized cutaneous paraneoplastic syndromes (PNS) are diagnosed during internal malignancies; however, the spectrum of keratinocyte skin neoplasms (KSC) related to PNS is still obscure. The aim of the present review is to compile and evaluate the literature data on PNS associated with a keratinocyte skin neoplasm (KSC). Employing Pubmed, MEDLINE was searched for KSC-associated PNS reports. Forty relevant entries were assembled, reporting a total of 41 PNS cases associated with a KSC (34 male). No review paper compiling this topic was found. Six distinct PNS entities were identified, and malignancy associated hypercalcemia (MAH; 78%), anemia (10%) and Bazex syndrome (5%) were the most frequently reported among them. 85% of the PNS were reported in association with SCC, 10% with BCC, and the rest with adnexal tumors. The median age of the patients at the time of PNS diagnosis was 58 years (range: five–83 years). In most cases the PNS was diagnosed either concurrently or after the KSC diagnosis. KSC predisposing conditions, as scars (22%) or hidradenitis suppurativa (20%), were reported in >70% of the PNS cases. Most PNS resolved after KSC treatment. In conclusion, PNS of a rather limited spectrum of entities are reported in association with KSC. They also seem to be rare, possibly reflecting a limited capacity of KSC to provoke overt PNS.


Introduction
Paraneoplastic syndromes (PNS) are nonmetastatic tumor-associated findings caused by malignancies in remote body sites [1,2]. PNS are found in a considerable fraction of tumor patients and may primarily affect the neuromuscular/musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, endocrine or renal systems [2]. Moreover, in some cases PNS may be even the first or most prominent manifestation of an underlying cancer, so their timely identification can guide the search for a still unrecognized malignancy. From a pathophysiologic point of view, most PNS are attributed to either endocrine phenomena (induced by tumor secreted biomolecules) or auto-immunity mediated immunological mechanisms [3,4]. Although the skin is a frequent target organ of PNS [5,6], PNS have been rather rarely reported in the course of skin neoplasms, even in relation to the biologically more aggressive ones, like malignant melanoma and Merkel cell carcinoma [7,8]. Herein, we compile the reported evidence of PNS associated with the growth of keratinocyte skin cancers (KSC). Our aim was to provide a typology of the spectrum of these PNS as an aid for the everyday clinical practice and as a basis for future comparative and mechanistic studies. To do so, we conducted a focused literature search and present our findings in the form of a research synthesis.

Materials and Methods
Only PNS attributed to KSC were included in this compilation, i.e., cutaneous squamous cell carcinomas (cSCC), basal cell carcinomas (BCC) and skin adnexal neoplasms. MEDLINE was searched using Pubmed  [2]. All authors analyzed the assembled material independently for reports of PNS and KSC (including stage and histology) as the only malignant disease in the history of the patient and results were merged. By evaluating the title/abstract information of the initially returned 831 papers we localized 53 articles with potentially relevant content for full-text search ( Figure 1). Of them, 15 were excluded (one was a duplicate publication, seven were cases of penile SCC, six were erroneously identified as reporting PNS in KSC and one reported no adequately personalized data) leaving to 39 papers reporting a total of 44 PNS cases associated with KSC . One paper ( [47]) referred to five cases with relevant findings, however without any personalized data, and was excluded from this compilation, resulting in 38 papers reporting 39 relevant cases. An additional search of the selected papers for similar material in MEDLINE via the Pubmed option "related links" did not yield any additional relevant material. A search based on the references lists of the selected publications yielded two additional relevant non-MEDLINE included publications [48,49], leading to a total of 40 papers reporting 41 PNS cases associated with KSC. The KSC were classified as primary, locally relapsed (after definite therapy and no evidence of metastases) or metastatic (with locoregional or distant metastases). Core clinical data of the 41 identified PNS cases in patients with KSC are compiled in Table 1 and are summarized by descriptive statistics.

Results
No review paper compiling the topic of KSC-associated PNS was found. Our literature search yielded only papers reporting solitary cases (40 papers reporting 41 PNS cases associated with KSC, Table 1). The core clinical features of the patients are compiled in Table 2 and stratified according to patients' gender and KSC type in Tables S1 and S2 (Supplementary Materials), respectively. Of the 41 patients with KSC-associated PNS, 34 were male (83%) and only seven were (17%) female. Thirty-five PNS cases (85%) were associated with cSCC, four with BCC (10%; one of them with squamous metaplasia) and two (5% each) with other KSC (trichilemmal carcinoma and pilomatrixoma; compare  (Table 3). Parathormone related protein (PTHrP) was increased in most cases with available data (20/21 cases), while parathormone (PTH) was either decreased (15/28 cases) or within normal range (13/28 cases). Phosphorus and 1.25(OH) 2 D 3 serum levels were in most cases either normal or decreased.  Other PNS included anemia in four patients (two cases of pure red cell aplasia), Bazex syndrome in two cSCC cases and three other syndromes (antiphospholipid syndrome, inflammatory arthralgias and neuropathy; Tables 1 and 2). Notably, different KSC entities tended to associate with different PNS: KSC of squamous phenotype (cSCC and adnexal tumors) with MAH (32/32 MAH cases) and BCC with anemia (3/4 cases, Table S2, Supplementary Materials).
Considering the timing of PNS manifestation, PNS was diagnosed in most cases (38/41 patients) either concurrently or after the KSC (Table 2). A KSC predisposing condition, local or systemic in the context of a genodermatosis, was reported in >70% of the PNS cases with available information (23/32 cases; Table 2). In 4/23 cases with a predisposing factor (17%) the predisposing condition was a genodermatosis and in 19/23 cases (83%) some acquired condition ( Table 2). Among the latter, scars (9 cases, 22%) and hidradenitis suppurativa (8 cases, 20%) were the most frequently associated conditions (Table 2). Finally, in most cases with available information, the PNS resolved after KSC treatment (25/38 cases, 66%, Table 2) The median age of the patients at the time of PNS diagnosis was 58 years (range: five-83 years; Table 4). Overall, patients with any condition predisposing to KSC were younger at the time of PNS diagnosis (median age: 50.0, range five-74 years) compared to the rest (median age: 68.5, range 25-83 years; Table 4). This was particularly true for patients with a genodermatosis (compare Table 1).

Discussion
Malignancy associated hypercalcemia (MAH) [50][51][52] was the PNS most frequently reported in patients with KSC. Serum calcium levels are rigorously regulated in health (normal range: 8.2-10.6 mg/dL), and depending on the degree of hypercalcemia a plethora of clinical findings may result, ranging from non-specific symptoms like asthenia, nausea, and loss of appetite for mild hypercalcemia to more specific presentations for calcium levels >12.0 mg/dL (confusion, lethargy, coma) and finally to shock and death for extremely high serum calcium levels (>18.0 mg/dL) [50]. Immediate medical attention is necessary in these cases to reduce serum calcium levels, restore the glomerular filtration rate, and treat the underlying KSC to allow for the resolution of the crisis.
Almost all KSC-associated MAH cases presented with laboratory profiles consistent with the diagnosis of humoral hypercalcemia of malignancy (HHM), a PNS seen in up to 20% of cancer patients in the course of their disease [50][51][52]. HHM is caused by ectopic secretion of PTHrP, an immunologically distinct member of the PTH polypeptides hormone family [51] that acts through the PTH receptor to induce ubiquitous bone resorption and to reduce renal calcium clearance and phosphorus reabsorption. Increased PTHrP serum levels were also reported in most MAH cases (including two hypercalcemia-leukocytosis cases) with relevant information in the presently compiled material (Table 3). PTHrP is secreted by normal and malignant human keratinocytes and seems to act as a paracrine factor during normal growth and differentiation of the epidermis [53]. It is worth noting that the scarcity of reports identified herein seems to confirm the clinical experience that hypercalcemia is only occasionally diagnosed in association with SCC of epidermal origin, and this contrasts with the fact that SCC arising in extracutaneous sites accounts for a substantial fraction of all MAH cases [51,54]. This latter finding is in accordance with the conclusion of a former study that hypercalcemia is rare in patients with KSC [47]. Remarkably, although a cSCC complicating a severe hidradenitis suppurativa case is a rather exceptional event, ref. [10] a substantial fraction of the present PNS cases (8/41 cases), particularly MAH (7/41 or 17% of all cases), were observed within this patient setting. As MAH may develop on the background of concurrency with some other hypercalcemia-predisposing condition, like a granulomatous disease [50], it is worth inquiring whether a granulomatous hidradenitis suppurativa variant [55] underlies the development of this PNS.
With four cases, anemia was the second most frequent PNS reported in patients with KSC. Anemia is probably the most common systemic finding of patients with solid tumors [56]. It is caused by either a functional iron deficiency (anemia of inflammation or chronic disease) or by iron sequestration. It is worth noting that most anemia cases were found in association with advanced BCC. Chronic bleeding from the large erosive tumor surfaces of advanced BCC could be a plausible anemia explanation; however, in two of the four KSC-associated cases (two of three BCC associated cases) the etiology of anemia was the rather rare pure red cell aplasia syndrome [57].
Bazex syndrome (acrokeratosis paraneoplastica), a rare obligate cutaneous PNS, [58] was the third more frequently reported PNS in association with a KSC. It is worth noting that although most cases in the literature are related to SCC of upper aerodigestive mucosae, cases compiled here are associated with cSCC of the extremities: a lower leg and a forearm tumor with axillary lymph node metastases.
A limitation of this review is the restriction of the literature source to Medline inclusions. However, this has most probably not affected the above conclusions since the compiled data set is rather representative of the topic.

Conclusions
Overall, patients with cSCC seem to be at a much higher risk to develop a PNS compared to BCC patients. Particularly, hypercalcemia in the setting of malignancy, related to increased PTHrP serum levels, was the most frequently reported PNS. It was seen almost exclusively in association with a cSCC. Physicians who care for patients with KSC should be alerted for this condition and adequately monitor susceptible patients to prevent a hypercalcemic crisis, an emergency condition which is associated with severe neurologic symptoms, poor prognosis, and decreased survival.
Taken together, descriptions of cases of KSC-associated PNS are rather scarcely reported in the medical literature. This is in distinct contrast with the high incidence of KSC, at least among Caucasians. Future studies should inquire whether KSC-associated PNS are truly rare events or whether they are simply underrecognized and consequently underreported conditions. In this context it could be interesting to compare the epidemiology of PNS in KSC with that of the other, non-keratinocyte derived skin cancers and also with keratinocyte tumors that originate from skin-adjacent mucosal surfaces (oropharynx, external genitalia). Nevertheless, we would like to predict that with the wider availability and application of the emerging treatment modalities for advanced KSC, the need to differentiate between adverse events and PNS will probably lead to increasing numbers of PNS observations in the future.